Previously, we confirmed that genetic elimination of the NMDARs in our mutant transgenic line begins at postnatal day 7 and is targeted to 4050% of cortical and hippocampal GABAergic cells, primarily parvalbumin positive ones. We showed an absence of NMDA receptor channel currents in virtually all of the targeted cells by whole-cell patch-clamp recordings, thus confirming via electrophysiology the functional knockout of this receptor. We then conducted an extensive battery of behavioral tests and found that the mutants exhibited a variety of schizophrenia-related phenotypes. Notably, the mutants exhibit positive symptoms such as psychomotor agitation and negative symptoms such as a reduced preference for sweet solution and deficits in nesting/mating, which mirror anhedonia and social withdrawal. In addition, the mutant mice have cognitive-like symptoms including impairments in spatial working memory and short-term social memory. Impaired sensorimotor gating, demonstrated by the decreased PPI of the startle reflex, was also observed. In addition, the NR1-deleted cortical GABAergic neurons exhibited reduced GAD67 and PV levels, consistent with reduced expression of these markers in the postmortem cortex of schizophrenic individuals. Disinhibition of cortical excitatory neurons and reduced neuronal synchrony in the mutants is also consistent with hyperactivity of the dorsolateral prefrontal cortex, a finding that was demonstrated during a working memory task in individuals with schizophrenia. Interestingly, many mutant phenotypes were first observed at an age of >12 weeks, suggesting there is a latency period between NR1 knockout and the emergence of these phenotypes. This latency period resembles the premorbid stage that precedes the emergence of symptoms, which is characteristic of several major psychiatric disorders, particularly schizophrenia. Social isolation-induced stress exacerbated the expression of these phenotypes in the mutant, similar to the stress-induced precipitation of psychiatric illnesses in humans and which is particularly well-characterized in schizophrenia. Notably, no such abnormalities were detected when the conditional knockout of NMDARs occurred after adolescence in the same cell population, suggesting a critical period for the development of psychiatric symptoms arising from dysregulation of inhibitory circuitry. These findings strongly support the notion that loss of NMDAR activity in cortical GABAergic interneurons during the early postnatal period leads to schizophrenia-related behavior. To identify how dysfunction of cortical inhibitory networks manifests at the cellular level, we are trying to elucidate the underlying molecular mechanisms that lead to schizophrenia-related phenotypes in the mutants. In particular, we are interested in stress-related regulation of GABA-mediated inhibition onto excitatory cells. Furthermore, by creating other interneuron-specific knockout mutants, we will try to dissect out the phenotypes into several signaling pathways. Through the development of this novel genetic system, we have been able to target a widely distributed GABAergic neural network and demonstrate that perturbations of this system may play a causal role in the onset of neuropsychiatric disorders.